Diffuse midline gliomas (DMG) are aggressive brain tumors with few treatment options that affect children and young adults. While recent genomic profiling of brain tumors has significantly enhanced our understanding of tumor biology, this knowledge has not yet translated to improved outcomes for patients with DMG. Given this lack of progress, there is a pressing need for innovative modeling approaches that faithfully recapitulate DMG. Here we discuss how a fusion of Cre/loxP genetic engineering and the RCAS/tv-a retroviral delivery system can be used to induce DMG tumors in mice. Notably, this platform allows tumors to occur alongside murine neurodevelopment while also preserving the immune system and genotypes of non-neoplastic cells, allowing for faithful study of tumor development and tumor-immune interactions, respectively.